Correction: Mouse Models of Intracerebral Hemorrhage in Ventricle, Cortex, and Hippocampus by Injections of Autologous Blood or Collagenase

Introduction: Local inflammation contributes to both brain injury and recovery after intracerebral hemorrhage (ICH). Our previous studies have shown brain-infiltrating macrophages (BIMs) aggravate early brain injury after ICH; however, BIMs increase scavenger receptor CD36 levels over time, and hematoma clearance is delayed in the absence of BIMs. The mechanism that mediates BIMs phenotypic change in the ICH brain is elusive. In this study, we delineate the dynamic transcriptome profile of BIMs after ICH and test potential mediator that might modulate BIMs polarity in ICH. Methods: Autologous blood injection ICH model and thrombin-treated bone marrow-derived macrophages (BMDM) were used to mimic ICH in vivo and in vitro . BIMs were isolated by FACS, and the 780 transcriptome of BIMs were determined using NanoString. Flow cytometry and RT-qPCR were performed to detect the frequency of phosphatidylserine-positive (eryptotic) RBCs and to assess BIMs phenotype in the perihematomal tissue. Erythrophagocytosis of eryptotic RBCs was identified by immunofluorescence and microscopy. Neurologic deficit was evaluated by cylinder test. Axl/Mer receptor tyrosine kinase double knockout (AM DKO) mice, AM DKO bone-marrow chimeras, and AM DKO BMDM were used to evaluate the function of Axl/Mer on macrophage phenotype and on brain recovery after ICH. Results: BIMs highly expressed proinflammatory transcripts such as cd86 , tlr2 , nlrp3 , and tnf at days 1 and 3 post-ICH; these were decreased at days 7 and 10. Transcripts relevant to efferocytosis ( axl ) and lysosome formation ( cd63 ) increased from days 3 to 10 post-ICH. At days 1 and 3, phosphatidylserine levels was increased on RBCs in the ICH brain. Engulfment of eryptotic RBCs reduced proinflammatory phenotype of BMDM. Thrombin-stimulated AM DKO BMDM had reduced erythrophagocytosis ability and increased tnf and il-6 gene expression. AM DKO mice and AM DKO chimeras had low CD36 and high MHC II levels on BIMs and had worse functional outcome after ICH. Conclusions: BIMs initially express proinflammatory phenotype and then switch to a reparative phenotype after ICH. Axl/Mer is involved in regulation of macrophage polarity through modulating erythrophagocytosis ability and contributes to ICH brain recovery.

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α7 Nicotinic Acetylcholine Receptor Stimulation Attenuates Neuroinflammation through JAK2-STAT3 Activation in Murine Models of Intracerebral Hemorrhage

BioMed Research International ◽

10.1155/2017/8134653 ◽

2017 ◽

Vol 2017 ◽

pp. 1-13 ◽

Cited By ~ 10

Author(s):

Paul R. Krafft ◽

Devin McBride ◽

William B. Rolland ◽

Tim Lekic ◽

Jerry J. Flores ◽

...

Keyword(s):

Intracerebral Hemorrhage ◽

Acetylcholine Receptor ◽

Nicotinic Acetylcholine Receptor ◽

Treatment Effects ◽

Autologous Blood ◽

Janus Kinase ◽

Intracerebral Injection ◽

Sprague Dawley ◽

Nicotinic Acetylcholine

Accounting for high mortality and morbidity rates, intracerebral hemorrhage (ICH) remains one of the most detrimental stroke subtypes lacking a specific therapy. Neuroinflammation contributes to ICH-induced brain injury and is associated with unfavorable outcomes. This study aimed to evaluate whetherα7 nicotinic acetylcholine receptor (α7nAChR) stimulation ameliorates neuroinflammation after ICH. Male CD-1 mice and Sprague-Dawley were subjected to intracerebral injection of autologous blood or bacterial collagenase. ICH animals received eitherα7nAChR agonist PHA-543613 alone or combined withα7nAChR antagonist methyllycaconitine (MLA) or Janus kinase 2 (JAK2) antagonist AG490. Neurobehavioral deficits were evaluated at 24 hours, 72 hours, and 10 weeks after ICH induction. Perihematomal expressions of JAK2, signal transducer and activator of transcription 3 (STAT3), tumor necrosis factor-α(TNF-α), and myeloperoxidase (MPO) were quantified via Western blot. Histologic volumetric analysis of brain tissues was conducted after 10 weeks following ICH induction. PHA-543613 improved short-term neurobehavioral (sensorimotor) deficits and increased activated perihematomal JAK2 and STAT3 expressions while decreasing TNF-αand MPO expressions after ICH. MLA reversed these treatment effects. PHA-543613 also improved long-term neurobehavioral (sensorimotor, learning, and memory) deficits and ameliorated brain atrophy after ICH. These treatment effects were reduced by AG490.α7nAChR stimulation reduced neuroinflammation via activation of the JAK2-STAT3 pathway, thereby ameliorating the short- and long-term sequelae after ICH.

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Celecoxib Induces Functional Recovery after Intracerebral Hemorrhage with Reduction of Brain Edema and Perihematomal Cell Death

Journal of Cerebral Blood Flow & Metabolism ◽

10.1097/01.wcb.0000130866.25040.7d ◽

2004 ◽

Vol 24 (8) ◽

pp. 926-933 ◽

Cited By ~ 125

Author(s):

Kon Chu ◽

Sang-Wuk Jeong ◽

Keun-Hwa Jung ◽

So-Young Han ◽

Soon-Tae Lee ◽

...

Keyword(s):

Cell Death ◽

Intracerebral Hemorrhage ◽

Brain Edema ◽

Functional Recovery ◽

Autologous Blood ◽

Prostaglandin E ◽

Dependent Manner ◽

Behavioral Tests ◽

Adult Rats ◽

Cox 2

The selective cyclooxygenase-2 (COX-2) inhibitor has been reported to have antiinflammatory, neuroprotective, and antioxidant effects in ischemia models. In this study, the authors examined whether a selective COX-2 inhibitor (celecoxib) reduces cerebral inflammation and edema after intracerebral hemorrhage (ICH), and whether functional recovery is sustained with longer treatment. ICH was induced using collagenase in adult rats. Celecoxib (10 or 20 mg/kg) was administered intraperitoneally 20 minutes, 6 hours, and 24 hours after ICH and then daily thereafter. Seventy-two hours after ICH induction, the rats were killed for histologic assessment and measurement of brain edema and prostaglandin E2. Behavioral tests were performed before and 1, 7, 14, 21, and 28 days after ICH. The brain water content of celecoxib-treated rats decreased both in lesioned and nonlesioned hemispheres in a dose-dependent manner. Compared with the ICH-only group, the number of TUNEL-positive, myeloperoxidase-positive, or OX42-positive cells was decreased in the periphery of hematoma and brain prostaglandin E2 level was reduced in the celecoxib-treated group. Celecoxib-treated rats recovered better by the behavioral tests at 7 days after ICH throughout the 28-day period, and the earlier the drug was administered, the better the functional recovery. Evidence of similar effects in an autologous blood–injected model showed that direct collagenase toxicity was not the major cause of inflammation or cell death. These data suggest that celecoxib treatment after ICH reduces prostaglandin E2 production, brain edema, inflammation, and perihematomal cell death in the perihematomal zone and induces better functional recovery.

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Autologous Blood Injection to Model Spontaneous Intracerebral Hemorrhage in Mice

Journal of Visualized Experiments ◽

10.3791/2618 ◽

2011 ◽

Cited By ~ 5

Author(s):

Lauren H. Sansing ◽

Scott E. Kasner ◽

Louise McCullough ◽

Puneet Agarwal ◽

Frank A. Welsh ◽

...

Keyword(s):

Intracerebral Hemorrhage ◽

Autologous Blood ◽

Spontaneous Intracerebral Hemorrhage ◽

Autologous Blood Injection ◽

Blood Injection

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Improvement in neurological outcome after administration of atorvastatin following experimental intracerebral hemorrhage in rats

Journal of Neurosurgery ◽

10.3171/jns.2004.101.1.0104 ◽

2004 ◽

Vol 101 (1) ◽

pp. 104-107 ◽

Cited By ~ 84

Author(s):

Donald Seyfried ◽

Yuxia Han ◽

Dunyue LU ◽

Jieli Chen ◽

Ali Bydon ◽

...

Keyword(s):

Intracerebral Hemorrhage ◽

Functional Outcome ◽

Autologous Blood ◽

Cell Loss ◽

Study Data ◽

Content Type ◽

Ipsilateral Striatum ◽

The Right ◽

Higher Doses ◽

Fine Print

Object. Atorvastatin, a β-hydroxy-β-methylglutaryl coenzyme A reductase inhibitor, improves neurological functional outcome, reduces cerebral cell loss, and promotes regional cellular plasticity when administered after intracerebral hemorrhage (ICH) in rats. Methods. Autologous blood was stereotactically injected into the right striatum in rats, and atorvastatin was administered orally beginning 24 hours after ICH and continued daily for 1 week. At a dose of 2 mg/kg, atorvastatin significantly reduced the severity of neurological deficit from 2 to 4 weeks after ICH. The area of cell loss in the ipsilateral striatum was also significantly reduced in these animals. Consistent with previous study data, higher doses of atorvastatin (8 mg/kg) did not improve functional outcome or reduce the extent of injury. Histochemical stains for markers of synaptogenesis, immature neurons, and neuronal migration revealed increased labeling in the region of hemorrhage in the atorvastatin-treated rats. Conclusions. Analysis of the data in this study indicates that atorvastatin improves neurological recovery after experimental ICH and may do so in part by increasing neuronal plasticity.

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Neurovascular Cell Sheet Transplantation in a Canine Model of Intracranial Hemorrhage

Cell Medicine ◽

10.3727/215517916x693384 ◽

2017 ◽

Vol 9 (3) ◽

pp. 73-85

Author(s):

Woo-Jin Lee ◽

Jong Young Lee ◽

Keun-Hwa Jung ◽

Soon-Tae Lee ◽

Hyo Yeol Kim ◽

...

Keyword(s):

Intracerebral Hemorrhage ◽

Cell Transplantation ◽

Therapeutic Potential ◽

Autologous Blood ◽

Cell Sheet ◽

Neural Tissue ◽

Direct Regeneration ◽

Saline Control ◽

Control Group ◽

Cell Based Therapy

Cell-based therapy for intracerebral hemorrhage (ICH) has a great therapeutic potential. However, methods to effectively induce direct regeneration of the damaged neural tissue after cell transplantation have not been established, which, if done, would improve the efficacy of cell-based therapy. In this study, we aimed to develop a cell sheet with neurovasculogenic potential and evaluate its usefulness in a canine ICH model. We designed a composite cell sheet made of neural progenitors derived from human olfactory neuroepithelium and vascular progenitors from human adipose tissue-derived stromal cells. We also generated a physiologic canine ICH model by manually injecting and then infusing autologous blood under arterial pressure. We transplanted the sheet cells (cell sheet group) or saline (control group) at the cortex over the hematoma at subacute stages (2 weeks from ICH induction). At 4 weeks from the cell transplantation, cell survival, migration, and differentiation were evaluated. Hemispheric atrophy and neurobehavioral recovery were also compared between the groups. As a result, the cell sheet was rich in extracellular matrices and expressed neurotrophic factors as well as the markers for neuronal development. After transplantation, the cells successfully survived for 4 weeks, and a large portion of those migrated to the perihematomal site and differentiated into neurons and pericytes (20% and 30% of migrated stem cells, respectively). Transplantation of cell sheets alleviated hemorrhage-related hemispheric atrophy ( p = 0.042) and showed tendency for improving functional recovery ( p = 0.062). Therefore, we concluded that the cell sheet transplantation technique might induce direct regeneration of neural tissue and might improve outcomes of intracerebral hemorrhage.

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Preconditioning with hyperbaric oxygen attenuates brain edema after experimental intracerebral hemorrhage

Neurosurgical FOCUS ◽

10.3171/foc.2007.22.5.14 ◽

2007 ◽

Vol 22 (5) ◽

pp. 1-6 ◽

Cited By ~ 21

Author(s):

Zhiyong Qin ◽

Shuijiang Song ◽

Guohua Xi ◽

Robert Silbergleit ◽

Richard F. Keep ◽

...

Keyword(s):

Intracerebral Hemorrhage ◽

Brain Edema ◽

Hyperbaric Oxygen ◽

Mapk Pathway ◽

Autologous Blood ◽

Neurosurgical Procedures ◽

Sprague Dawley ◽

Edema Formation ◽

Group 2 ◽

Brain Edema Formation

Object Preconditioning with hyperbaric oxygen (HBO2) reduces ischemic brain damage. Activation of p44/42 mitogen-activated protein kinases (p44/42 MAPK) has been associated with preconditioning-induced brain ischemic tolerance. This study investigated if preconditioning with HBO2 protects against intracerebral hemorrhage (ICH)–induced brain edema formation and examined the role of p44/42 MAPK in such protection. Methods The study had three experimental groups. In Group 1, Sprague-Dawley rats received two, three, or five consecutive sessions of preconditioning with HBO2 (3 ata, 100% xygen, 1 hour daily). Twenty-four hours after preconditioning with HBO2, rats received an infusion of autologous blood into the caudate. They were killed 1 or 3 days later for brain edema measurement. Rats in Group 2 received either five sessions of preconditioning with HBO2 or control pretreatment and were killed 24 hours later for Western blot and immunohistochemical analyses. In Group 3, rats received an intracau-date injection of PD098059 (an inhibitor of p44/42 MAPK activation) before the first of five sessions of preconditioning with HBO2. Twenty-four hours after the final preconditioning with HBO2, rats received an intracaudate blood infusion. Brain water content was measured 24 hours after ICH. Results Fewer than five sessions of preconditioning with HBO2 did not significantly attenuate brain edema after ICH. Five sessions of preconditioning with HBO2 reduced perihematomal edema 24 and 72 hours after ICH (p < 0.05). Strong p44/42 MAPK immunoreactivity was detected in the basal ganglia 24 hours after preconditioning with BO2. Intracaudate infusion of PD098059 abolished HBO2preconditioning–induced protection against ICH-induced brain edema formation. Conclusions Preconditioning with HBO2 protects against brain edema formation following ICH. Activation of the p44/42 MAPK pathway contributes to that protection. Preconditioning with HBO2 may be a way of limiting brain injury during invasive neurosurgical procedures that cause bleeding.

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Lesional and perilesional tissue characterization by automated image processing in a novel gyrencephalic animal model of peracute intracerebral hemorrhage

Journal of Cerebral Blood Flow & Metabolism ◽

10.1177/0271678x18802119 ◽

2018 ◽

Vol 39 (12) ◽

pp. 2521-2535 ◽

Cited By ~ 6

Author(s):

Johannes Boltze ◽

Fabienne Ferrara ◽

Atticus H Hainsworth ◽

Leslie R Bridges ◽

Marietta Zille ◽

...

Keyword(s):

White Matter ◽

Animal Models ◽

Intracerebral Hemorrhage ◽

Autologous Blood ◽

Hematoma Expansion ◽

Intracerebral Hematoma ◽

Cerebral White Matter ◽

Large Animal ◽

Adult Sheep ◽

Large Animal Models

Intracerebral hemorrhage (ICH) is an important stroke subtype, but preclinical research is limited by a lack of translational animal models. Large animal models are useful to comparatively investigate key pathophysiological parameters in human ICH. To (i) establish an acute model of moderate ICH in adult sheep and (ii) an advanced neuroimage processing pipeline for automatic brain tissue and hemorrhagic lesion determination; 14 adult sheep were assigned for stereotactically induced ICH into cerebral white matter under physiological monitoring. Six hours after ICH neuroimaging using 1.5T MRI including structural as well as perfusion and diffusion, weighted imaging was performed before scarification and subsequent neuropathological investigation including immunohistological staining. Controlled, stereotactic application of autologous blood caused a space-occupying intracerebral hematoma of moderate severity, predominantly affecting white matter at 5 h post-injection. Neuroimage post-processing including lesion probability maps enabled automatic quantification of structural alterations including perilesional diffusion and perfusion restrictions. Neuropathological and immunohistological investigation confirmed perilesional vacuolation, axonal damage, and perivascular blood as seen after human ICH. The model and imaging platform reflects key aspects of human ICH and enables future translational research on hematoma expansion/evacuation, white matter changes, hematoma evacuation, and other aspects.

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IL (Interleukin)-15 Bridges Astrocyte-Microglia Crosstalk and Exacerbates Brain Injury Following Intracerebral Hemorrhage

Stroke ◽

10.1161/strokeaha.119.028638 ◽

2020 ◽

Vol 51 (3) ◽

pp. 967-974 ◽

Cited By ~ 9

Author(s):

Samuel X. Shi ◽

Yu-Jing Li ◽

Kaibin Shi ◽

Kristofer Wood ◽

Andrew F. Ducruet ◽

...

Keyword(s):

Brain Injury ◽

Intracerebral Hemorrhage ◽

Autologous Blood ◽

Brain Slices ◽

Neurological Deficits ◽

Transgenic Mouse Line ◽

Il Interleukin ◽

Targeted Expression ◽

Interleukin 15

Background and Purpose— Microglia are among the first cells to respond to intracerebral hemorrhage (ICH), but the mechanisms that underlie their activity following ICH remain unclear. IL (interleukin)-15 is a proinflammatory cytokine that orchestrates homeostasis and the intensity of the immune response following central nervous system inflammatory events. The goal of this study was to investigate the role of IL-15 in ICH injury. Methods— Using brain slices of patients with ICH, we determined the presence and cellular source of IL-15. A transgenic mouse line with targeted expression of IL-15 in astrocytes was generated to determine the role of astrocytic IL-15 in ICH. The expression of IL-15 was controlled by a glial fibrillary acidic protein promoter (GFAP-IL-15 tg ). ICH was induced by intraparenchymal injection of collagenase or autologous blood. Results— In patients with ICH and wild-type mice subjected to experimental ICH, we found a significant upregulation of IL-15 in astrocytes. In GFAP-IL-15 tg mice, we found that astrocyte-targeted expression of IL-15 exacerbated brain edema and neurological deficits following ICH. This aggravated ICH injury in GFAP-IL-15 tg mice is accompanied by increased microglial accumulation in close proximity to astrocytes in perihematomal tissues. Additionally, microglial expression of CD86, IL-1β, and TNF-α is markedly increased in GFAP-IL-15 tg mice following ICH. Furthermore, depletion of microglia using a colony stimulating factor 1 receptor inhibitor diminishes the exacerbation of ICH injury in GFAP-IL-15 tg mice. Conclusions— Our findings identify IL-15 as a mediator of the crosstalk between astrocytes and microglia that exacerbates brain injury following ICH.

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